Cyclin Dependent Kinase 5 (Cdk5) (eBook)

Preface 5
Contents 7
Contributors 9
About the Editors 15
Cdk5/p35 Regulates Neuronal Migration 17
Expression of Cdk5, p35, and p39 During Brain Development 17
Cdk5/p35 Deficiency Causes Neuronal Migration Defects in CNS 18
Normal Migration of Cortical Neurons and Alteration by Cdk5/ p35 Deficiency 19
Molecular Mechanism of the Regulatory Function of Cdk5/p35 in Neuronal Migration 20
Summary 22
References 22
CRMP Family Protein: Novel Targets for Cdk5 That Regulates Axon Guidance, Synapse Maturation, and Cell Migration 25
Introduction 26
Fyn and Cdk5 Are Involved in Sema3A Signaling 27
Plex-A2 Associates with Cdk5 via Interaction with Active Fyn, and Fyn Activates Cdk5 via Tyr15 Phosphorylation 28
Sema3A-Induced Growth Cone Collapse Is Mediated Through Cdk5 Activation via Tyr15 Phosphorylation 29
CRMP2 Is an In Vivo Substrate of Cdk5 30
Cdk5-Primed GSK3beta Phosphorylation of CRMP2 31
The Phosphorylation of CRMPs Disrupts Association of CRMPs with Tubulin 32
Sema3A-Induced Growth Cone Collapse Through Phosphorylation of CRMP2, and Evidence for Both CRMP1 and CRMP2 Are Involved in Sema3A Signaling 33
CRMP1 Regulates Spine Maturation Through Mediating Sema3A Signaling In Vivo 35
CRMP1 Mediates Reelin Signaling in Cortical Neuronal Migration 36
The Phosphorylation of CRMPs in Mediating Extacellular Signals 37
Conclusion 37
References 38
Cdk5 in Presynapses 41
Cdk5 in Presynapses 41
Cdk5 in Exocytosis 41
Cdk5 and Synapsin 42
Cdk5 and Munc-18 42
Cdk5 and Voltage-Gated Calcium Channels 43
Role of Cdk5 in Exocytosis 44
Cdk5 in Endocytosis 44
Cdk5 and Dynamin 1 44
Cdk5 and Amphiphysin 45
Cdk5 and Synaptojanin 46
Concluding Remarks 46
References 46
Cyclin-Dependent Kinase 5: A Critical Regulator of Neurotransmitter Release 50
Introduction 50
Effect of Cdk5 on the Exocytosis of Synaptic Vesicles in Presynaptic Terminals 53
Phosphorylation of Munc18-1 by Cdk5 54
Phosphorylation of Sept5 by Cdk5 55
Phosphorylation of Synapsin 1 by Cdk5 56
Phosphorylation of Pctaire1, a Kinase to Phosphorylate NSF by Cdk5 56
Effect of Cdk5 on Endocytosis in Presynaptic Terminals 57
Phosphorylation of Dynamin 1 by Cdk5 58
Phosphorylation of Amphiphysin I by Cdk5 58
Phosphorylation of Synaptojanin 1 by Cdk5 59
Effect of Cdk5 on Neurotransmitter Synthesis 59
Phosphorylation of Tyrosine Hydroxylase by Cdk5 59
Control of Presynaptic Ca and Lipid Signaling by Cdk5 60
Phosphorylation of P/Q-Type Calcium Channels by Cdk5 60
Phosphorylation of PIPKIgamma by Cdk5 61
Conclusion 61
References 62
Cdk5 in Dendrite and Synapse Development: Emerging Role as a Modulator of Receptor Tyrosine Kinase Signaling 66
Dendrite, Spine, and Synapse Development 66
Cdk5: an Atypical Cyclin-Dependent Kinase 68
Regulation of Dendrite Development by Cdk5 68
Cdk5 as a Modulator of Extracellular Cues 69
Neurotrophins 69
Semaphorin 3A 71
Cdk5: Regulator of Cytoskeletal Components 72
Regulation of Actin Dynamics Through Modulation of Rho GTPases 72
Regulation of Microtubule Dynamics 73
Regulation of Synapse Formation by Cdk5 73
Regulation of Neurotransmitter Receptor Expression 75
Cdk5 as a Modulator of Extracellular Cues Signaling 75
Regulation of Gene Transcription Machinery by Cdk5 75
Regulation of Neurotransmitter Receptor Clustering 76
Regulation of Spine Development 76
Regulation of Spine Morphology Through Modulation of Extracellular Cues and Rho GTPase 77
Regulation of Spine Morphology Through Modulating Synaptic Activity 77
Cdk5: Modulator of RTK Signaling 78
References 80
Cyclin-Dependent Kinase 5 (Cdk5) Modulates Signal Transduction Pathways Regulating Neuronal Survival 84
Introduction 84
Cdk5-MAPK Cross Talk 87
Inhibition of Cdk5 Activity Induces Neuronal Apoptosis by Increased and Sustained Erk1/2 Activation 91
Cdk5-JNK3 Cross Talk 92
Cdk5 Phosphorylates JNK3 92
Cdk5 Phosphorylation of JNK3 Inhibits c-Jun Phosphorylation 94
Cdk5-Receptor Tyrosine Kinase (Erb2/3) Cross Talk 95
Other Signaling Pathways Regulated by Cdk5 98
Cdk5 and GSK3 Cross Talk Affects Fast Axonal Transport 98
Cdk5-RasGRF Cross Talk, Upstream of the MAPK Pathway 99
Concluding Remarks 100
References 102
CDK5 and Mitochondrial Cell Death Pathways 106
Programmed Cell Death 106
Apoptosis in Neuronal Cells 107
Mitochondrial Apoptosis Pathways and CDK5 Toxicity 108
Dynamics of Mitochondrial Morphology 110
The Mitochondrial Fission Machinery 111
The Mitochondrial Fusion Machinery 112
Mitochondrial Morphology During Neuronal Apoptosis 113
Regulation of Mitochondrial Fission by CDK5 115
Mitochondrial CDK5 Substrates 117
Summary 117
References 118
Regulation and Function of Cdk5 in the Nucleus 122
Introduction 122
Detection of Cdk5 and Its Activators in the Nucleus 123
Nuclear Function of Cdk5 and p35 124
Nuclear Transcription Factors Targeted by Cdk5 125
Non-Transcription Factor Targets of Cdk5 in the Nucleus 128
Regulation of Nuclear Cdk5 and Its Activators 129
Regulation of the Level and Nuclear Localization of p35 and p25 129
Association of Cdk5 with Cyclins 130
Final Remarks 131
References 131
Cdk5 May Be an Atypical Kinase, but Not in the Way You Think 134
Introduction 134
The Cyclin-Dependent Kinase Family 134
Cyclin-Dependent Kinases and Normal Cell Cycle Regulation 135
Regulation of Cyclin-Dependent Kinases 136
Cell Cycle Regulation in Post-Mitotic Neurons 137
Development and In Vitro Systems 137
Aberrant Cell Cycle Events in Neurodegenerative Diseases 138
Cell Cycle Events in Mouse Disease Models 139
Cdk5: An Atypical CDK 140
The Regulation of Cdk5 140
Function of Cdk5 141
The Roles of Cdk5 in the Adult 141
Synapse Function 141
Neuronal Survival 141
The Roles of Cdk5 in Development 142
Migration 142
Survival 142
Cdk5 and the Cell Cycle Regulation in Neurons 143
Conclusion and Perspectives 146
References 147
Cdk5 and Neuregulin-1 Signaling 153
References 157
Cyclin-Dependent Kinase 5 and Insulin Secretion 159
Glucose Stimulation/Insulin Secretion Coupling in the Pancreatic beta-Cell 160
Regulated Exocytosis of Insulin 161
Cdk5 in Pancreatic beta-Cells 163
Cdk5/p39 in Insulin Exocytosis and beta-cell Physiology 165
Is Cdk5 Positively or Negatively Regulating Insulin Secretion? 167
References 169
Protein-Protein Interactions Involving the N-Terminus of p35 173
Introduction 173
N-Terminus of p35 Interacts with Various Proteins 174
Regulation of Cdk5 Activation 175
Nuclear Import of p35 176
Cdk5-p35 in the Control of S6 Kinase 1 Activation 178
Regulation of Microtubule Organization 179
Conclusion 182
References 182
The Kinase Activity of Cdk5 and Its Regulation 185
Introduction 185
Kinase Properties of Cdk5 186
Cdk5 Activated by p35 or its N-Terminal Truncated Form p25 186
Cdk5 Activated by p39 189
Effects of the N-terminal p10 Domain on the Kinase Activity of Cdk5 191
Regulation of Cdk5 Activity 193
Considerations from the Activation Mechanisms of Cdk1-Cyclin B in Proliferating Cells 193
Regulation of Cdk5 Activity by Synthesis and Degradation of p35 195
Regulation of Cdk5 Activity by Phosphorylation 197
Protein Modulators of Cdk5 Activity 198
Suppression of the Cdk5 Activity by Membranes 198
Summary 199
References 199
The Structural Bases of CDK5 Activity 205
Introduction 205
Regulation of Protein Kinases: General Remarks 206
Structure of the ePK Catalytic Domain 207
Conformational Regulation of Kinase Activity 211
CDK5: Structural Considerations 213
The Inhibition of CDK5 216
The Substrate Specificity of CDK5 217
Web Resources 219
References 219
Cdk5, a Journey from Brain to Pain: Lessons from Gene Targeting 225
Cdk5 Knockout (Cdk5-/-) Mice 226
Cdk5 Chimeric Mice (Cdk5-/- lrarrCdk5plus1/plus1) 227
Cdk5 Overexpressing Transgenic (TgCdk5) Mice 228
Cdk5 Overexpression Under the Control of p35 Promoter in Cdk5-null (TgKO) Mice 228
p35 Knockout (p35-/-) Mice 229
p35 Knockout and Cdk5 Heterozygous Mice (p35-/- Cdk5plus1/-)
p35 Overexpressing Transgenic (Tgp35) Mice 230
p35 Overexpression Under a p35 Promoter in p35-null (Tgp35 p35-/-) Mice
p25 Expressing Transgenic (p25-tg) Mice 231
Inducible Transgenic Mice Overexpressing p25 in the Postnatal Forebrain 231
Low Expression of the p25 Transgene Under the NSE Promoter in p35-null (p35-/- p25-tg) Mice
p39 Knockout (p39-/-) Mice 233
p35 and p39 Double Knockout (p35-/- p39-/-) Mice
Cdk5 Floxed (Cdk5f/f) Mice 234
Cdk5 and Pain 235
References 238
Involvement of Cdk5 in Synaptic Plasticity, and Learning and Memory 241
Introduction 241
Molecular Mechanisms of Synaptic Plasticity 242
Pre-synaptic Mechanisms 247
Post-synaptic Mechanisms 252
Extra-Synaptic Mechanisms 255
Cdk5 in Cellular Mechanisms of Synaptic Plasticity 256
Short-Term Plasticity 258
Long-Term Plasticity 259
Cdk5 in Learning and Memory 262
Putative Mechanisms Underlying Cdk5-Mediated Effects in Synaptic Plasticity, and Learning and Memory 265
Conclusion 266
References 267
Cyclin-Dependent Kinase 5 (Cdk5): Linking Synaptic Plasticity and Neurodegeneration 275
Synaptic Plasticity, Learning, and Memory 275
Cdk5 is a Novel Regulator of Synaptic Plasticity 277
Deregulated Cdk5 Activity is Implicated in Neurodegenerative Diseases 282
p25 as a Plasticity Factor 286
References 289
Cdk5 as a Drug Target for Alzheimer’s Disease 297
Introduction 297
CDK5 in Tau Hyperphosphorylation 299
Beyond Tau Hyperphosphorylation 301
Safety of Cdk5 Inhibitors 303
References 306
Index 314